Despite recent advances in the treatment of acute myocardial infarction (MI), attempts to repair extensive myocardial damage and to treat heart failure are often met with limited success. One of the reasons for the lack of success is that the myocardium is unable to regenerate because cardiomyocytes do not have the capacity for replication after injury, and furthermore because there are apparently no muscle stem cells in the myocardium.
Existing strategies for restoring heart function after myocardial injury are practically limited to cardiac transplantation. Since the supply of donor hearts is limited, tissue engineering appears to be a promising approach for the formation of new functional tissue to replace lost or failing tissue. Earlier studies indicated the possibility of transplanting isolated cardiomyocytes or myoblasts in order to enhance cardiac function following myocardial injury (Taylor et al., Nat. Med., 4:929–33, 1998). However, this approach does not permit the formation of tissue-engineered cardiac biografts having the desired shape, size and consistency.
A bioengineered cardiac graft using fetal myocardial cells contained within a gelatin mesh was recently disclosed (Li et al., Circulation 19, 63–69, 1999). When transplanted into rodent post-infarction myocardial tissue, however, no improvement in cardiac function could be observed. A similar method for producing a myocardial graft in a mammal using scaffolding is disclosed in U.S. Pat. No. 6,099,832. In said patent, cardiomyocytes were either directly introduced into a cryo-damaged myocardial tissue, or were first suspended on scaffolding polymers prior to transplantation. In both cases, the biograft did not provide tissue characteristics such as cell—cell interactions and the formation of extracellular matrix. In addition, the methods of U.S. Pat. No. 6,099,832 do not provide the ability to determine the composition and consistency of the biograft.
In WO 99/03973, mesenchymal stem cells were supported onto a semi-solid or solid matrix, such as collagen and its derivatives, polylactic acid or polyglycolic acid, and rapidly injected into the tissue. However, cells were not implanted within a scaffolding-type matrix prior to transplantation, and therefore there was no creation of tissue-engineered cardiac biograft prior to transplantation.
In WO 97/44070 of the same applicants hereof, the specification of which is incorporated herein by reference, a new method for the preparation of three-dimensional, porous, biodegradable sponges made from polysaccharides is disclosed.
In WO 99/65463 of the same applicants hereof, the specification of which is incorporated herein by reference, a device for the delivery of drugs to mucosal or luminal surfaces using a porous matrix is disclosed. According to a preferred embodiment of said delivery device, the porous matrix comprises an alginate scaffold. However, said porous matrix was used only for mucosal drug delivery.
It has now been surprisingly found, and this is an object of the present invention, that cultured mammalian cells may be grown in vitro in porous three-dimensional alginate scaffolds, leading to the formation of tissue-engineered biografts, said biografts possessing the characteristics of myocardial tissue, including the formation of cell—cell interactions, contractility and extracellular matrix components. Said tissue-engineered biografts may be used for repairing damaged myocardial tissue by transplanting them onto said myocardial tissue.
It is a purpose of the present invention to provide a tissue-engineered cardiac biograft system for use in replacing the scar tissue that is formed following myocardial infarction.
It is a further object of the invention to provide a tissue-engineered cardiac biograft system that is useful for improving impaired cardiac functions following myocardial infarction.
Other objects and advantages of the invention will become apparent as the description proceeds.